Clinical Onset and Multiple Sclerosis Relapse after SARS-CoV-2 Infection

Round 1

Reviewer 1 Report

The manuscript is about post SARS-CoV-2 CNS inflammation and MS exacerbation in known case of MS.

I will suggest author to present this manuscript as case report and review of literature as there are various recent literature on this topic here are few examples. Including CNS demyelination disorder post COVID-19 vaccination

100287. Kataria S, Tandon M, Melnic V, Sriwastava S. A case series and literature review of multiple sclerosis and COVID-19: Clinical characteristics, outcomes and a brief review of immunotherapies. eNeurologicalSci. 2020 Dec;21:100287. doi: 10.1016/j.ensci.2020.100287. Epub 2020 Nov 2. PMID: 33163634; PMCID: PMC7605741

14. Khayat-Khoei M, Bhattacharyya S, Katz J, Harrison D, Tauhid S, Bruso P, Houtchens MK, Edwards KR, Bakshi R. COVID-19 mRNA vaccination leading to CNS inflammation: a case series. J Neurol. 2021 Sep 4:1–14. doi: 10.1007/s00415-021-10780-7. Epub ahead of print. PMID: 34480607; PMCID: PMC8417681.

For case1: The csf protein values please confirm the unit and values the level 574 mg/dl is too high may be the author wanted to say 57.4mg/dl?

It will be also important to add the values of oligoclonal bands.

Also, what was the overall plan in terms of management for the first case was patient initiated on DMT or not.

For case 2: It appears post viral exacerbation of MS. I will like to have literature to support that post covid sequalae can present beyond 6 months as patient has sars-cov-2 igg positive in July 2020 and mri showed new lesion in June 2021.

Author Response

We thank the reviewers for their suggestions. We addressed a point by point answer to their comments.

Changes in the manuscript are highlighted in bold characters.

We also reviewed the paper for typos and language and modified it consequently.

Reviewer 1. 

# 1. I will suggest author to present this manuscript as case report and review of literature as there are various recent literature on this topic here are few examples. Including CNS demyelination disorder post COVID-19 vaccination.

Kataria S, Tandon M, Melnic V, Sriwastava S. A case series and literature review of multiple sclerosis and COVID-19: Clinical characteristics, outcomes and a brief review of immunotherapies. eNeurologicalSci. 2020 Dec;21:100287. doi: 10.1016/j.ensci.2020.100287.

Khayat-Khoei M, Bhattacharyya S, Katz J, Harrison D, Tauhid S, Bruso P, Houtchens MK, Edwards KR, Bakshi R. COVID-19 mRNA vaccination leading to CNS inflammation: a case series. J Neurol. 2021 Sep 4:1–14.

According to the suggestions made, we updated the reference list. Moreover, the discussion section was modified adding the following sentences: 

"A recent report for instance, described a case series of MS symptoms worsening occurring after vaccination against COVID-19. The authors underlined however, that in their case series description there was no background knowledge of the amount of patients who underwent to vaccination in the same period. Moreover, they did not performed comparisons with the rate of relapses among patients who did not received Covid vaccination. In our MS center, over more than 300 hundred individuals with MS who underwent to COVID-19 vaccination we observed only one possible disease relapse occurring during the month following vaccination (Khayat-Khoei M, et al. 2021). (Kataria S, et al 2020) .

“Another study reported MS worsening occurring in three patients after COVID-19 infection without a clear confirmation of a preceding relapse. The authors concluded that MS worsening could be attributable to pseudo-relapses associated to the acute infection (Kataria S, et al 2020).”

#2 For case1: The csf protein values please confirm the unit and values the level 574 mg/dl is too high may be the author wanted to say 57.4mg/dl?

There was a typo error; the correct value is 574 mg/L. We modified the sentence accordingly. 

#3 It will be also important to add the values of oligoclonal bands.

 We added the OG value as requested.

#4 Also, what was the overall plan in terms of management for the first case was patient initiated on DMT or not.

The following sentence was added at the end of case 1 description: “At the end of the diagnostic work-up the patients, considering  also the cardiological comorbidity, was started on pegilated beta interferon”.

 # 5 For case 2: It appears post viral exacerbation of MS. I will like to have literature to support that post covid sequalae can present beyond 6 months as patient has sars-cov-2 igg positive in July 2020 and mri showed new lesion in June 2021.

We understand that the sentence regarding the second case was misleading. In fact the interval between Covid infection and disease worsening was within the two months following the infection. Follow-up MRI and Serum detection for anti spike antibodies were both performed in January 2021.

We modified therefore, the case description as follows:  "In January 2021 (two moths after COVID-19) the follow-up MRI , showed multiple new active lesions in the supratentorial white matter ….”.

Reviewer 2 Report

This paper described two cases of patients, showing MS disease onset and MS relapse after COVID-19 infection.

Abstract: The presented data did not support the importance of vaccination in individuals with multiple sclerosis. It just explain the COVID-19 will induce MS attack and relapse.

Did you perform a facial stimulation test or blink reflex to exam facial palsy in case 1? Did any brainstem lesion related to CN7 involve? What did the SSEP result show initially with normal limitation or decrease?

Vaccine will also induce MS relapse, the conclusion did not support it. It suggested moving to discussion. The vaccine just reduced COVID-19 infection rather than MS.

Author Response

We thank the reviewer for his revision of the manuscript.

We addressed a point by point answer to their comments.

Changes in the manuscript are highlighted in bold characters.

We also reviewed the paper for typos and language and modified it consequently.

This paper described two cases of patients, showing MS disease onset and MS relapse after COVID-19 infection.

#1. Abstract: The presented data did not support the importance of vaccination in individuals with multiple sclerosis. It just explain the COVID-19 will induce MS attack and relapse.

We agree with the reviewer; aim of this report was actually, to give strength to guidelines strongly supporting vaccination against COVID-19. For this reason we reported the examples of patients either presenting with onset or relapse of MS after covid infection.

As already suggested by reviewer 1, the paper was modified as highlighted in the manuscript adding new references about disease worsening after infection or vaccination and adding also briefly, the experience of our MS center regarding immunization against COVID-19.

#2. Did you perform a facial stimulation test or blink reflex to exam facial palsy in case 1? Did any brainstem lesion related to CN7 involve? What did the SSEP result show initially with normal limitation or decrease?

As reported auditory evoked potentials somatosensory evoked responses are in the normal ranges; the semiological characterization of the facial palsy was based indeed on the neurological examination. However, MRI showed widespread white matter involvement as described including several periventricular, internal capsule, and brain stem lesions.

#3. Vaccine will also induce MS relapse, the conclusion did not support it. It suggested moving to discussion. The vaccine just reduced COVID-19 infection rather than MS.

We are not sure about this reviewer’s comment. Our opinion, as reported in the discussion, is in the same perspective of EAN recommendation supporting the importance of vaccinating individuals with MS against covid-19. As we wrote in discussion section there are not actually, enough evidence supporting risks related to immunization including those against COVID-19 in people with MS. Of course it is not the aim of this report to evaluate the possible effects of vaccination in reducing MS risk nor disease progression.

Kind regards,

Paolo Ragonese

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

There were some cases of Multiple Sclerosis Relapse After COVID-19 Vaccination

doi:10.3389/fneur.2021.721502

doi:10.3389/fneur.2021.765954

Please delete "vaccination against SARS-CoV-2 should not be delayed in conclusion." or modify the description.

Author Response

According to reviewers' suggestion we modified the sentence as follows:

"We conclude hence, that given the unpredictable disease course in patients who develop SARS-CoV-2 infection and the risk for relapses determined by COVID-19 disease compared to the low rate of relapses after vaccination, immunization against SARS-COV-2 should be recommended in individuals with MS."